TY - JOUR
T1 - A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3
AU - Kaplan, Robert C.
AU - Petersen, Ann Kristin
AU - Chen, Ming Huei
AU - Teumer, Alexander
AU - Glazer, Nicole L.
AU - DÖring, Angela
AU - Lam, Carolyn S.P.
AU - Friedrich, Nele
AU - Newman, Anne
AU - Müller, Martina
AU - Yang, Qiong
AU - Homuth, Georg
AU - Cappola, Anne
AU - Klopp, Norman
AU - Smith, Holly
AU - Ernst, Florian
AU - Psaty, Bruce M.
AU - Wichmann, H. Erich
AU - Sawyer, Douglas B.
AU - Biffar, Reiner
AU - Rotter, Jerome I.
AU - Gieger, Christian
AU - Sullivan, Lisa S.
AU - Völzke, Henry
AU - Rice, Kenneth
AU - Spyroglou, Ariadni
AU - Kroemer, Heyo K.
AU - Ida Chen, Y. D.
AU - Manolopoulou, Jenny
AU - Nauck, Matthias
AU - Strickler, Howard D.
AU - Goodarzi, Mark O.
AU - Reincke, Martin
AU - Pollak, Michael N.
AU - Bidlingmaier, Martin
AU - Vasan, Ramachandran S.
AU - Wallaschofski, Henri
PY - 2011/3
Y1 - 2011/3
N2 - Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 3 10 -8 (P = 3.3 × 10 -101). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10 -26). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10 -21) and higher IGF-I (P = 4.9 × 10 -9) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10 -11, IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10 -10, SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10 -7), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.
AB - Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 3 10 -8 (P = 3.3 × 10 -101). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10 -26). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10 -21) and higher IGF-I (P = 4.9 × 10 -9) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10 -11, IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10 -10, SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10 -7), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.
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U2 - 10.1093/hmg/ddq560
DO - 10.1093/hmg/ddq560
M3 - Article
C2 - 21216879
AN - SCOPUS:79952015071
SN - 0964-6906
VL - 20
SP - 1241
EP - 1251
JO - Human molecular genetics
JF - Human molecular genetics
IS - 6
M1 - ddq560
ER -
